The natural hormone, 1α,25-dihydroxyvitamin D3 (also referred to as 1α,25-dihydroxycholecalciferol and calcitriol) and its analog in the ergosterol series, i.e. 1α,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins, and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies. The structure of 1α,25-dihydroxyvitamin D3 and the numbering system used to denote the carbon atoms in this compound are shown below.

Another class of vitamin D analogs, i.e. the so called 19-nor-vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
Various 2-substituted analogs of 1α,25-dihydroxy-19-nor-vitamin D3 have also been synthesized, i.e. compounds substituted at the 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), with 2-alkyl groups (DeLuca et a., U.S. Pat. No. 5,945,410), and with 2-alkylidene groups (DeLuca et al., U.S. Pat. No. 5,843,928), which exhibit interesting and selective activity profiles. All these studies indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
U.S. Pat. No. 4,666,634 discloses 2β-hydroxy and alkoxy (e.g., ED-71) analogs of 1α,25-dihydroxyvitamin D3 as potential drugs for use in treating osteoporosis and for use as antitumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989). Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkyl groups) A-ring analogs of 1α,25-dihydroxyvitamin D3 have been prepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner et al, J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617 (1995)).
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, their analogs which are characterized by the transposition of the ring A exocyclic methylene group from carbon 10 (C-10) to carbon 2 (C-2), i.e. 2-methylene-19-nor-vitamin D compounds have been recently synthesized and tested (Sicinski et al., J. Med. Chem., 41, 4662 (1998); Sicinski et al., Steroids 67, 247 (2002); DeLuca et al., U.S. Pat. Nos. 5,843,928, 5,936,133 and 6,382,071). Molecular mechanics studies, performed on these analogs, showed that a change of ring-A conformation can be expected resulting in the “flattening” of the cyclohexanediol ring. From molecular mechanics calculations and NMR studies of these compounds, the A-ring conformational equilibrium was established to be about 6:4 in favor of the conformer that has an equatorial 1α-OH. Introduction of the 2-methylene group into the 19-nor-vitamin D carbon skeleton changes the character of its (1α- and 3β-) A-ring hydroxyl groups; they are both now in the allylic positions, similar to the 1 a-hydroxyl group (important for biological activity) in the natural hormone, 1α,25-(OH)2D3. 1α,25-Dihydroxy-2-methylene-19-norvitamin D analogs are characterized by significant biological potency which is enhanced in compounds with the “unnatural” (20S)-configuration.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, analogs which are characterized by the presence of a methylene substituent at carbon 2 (C-2), a hydroxyl group at carbon 1 (C-1), and a shortened side chain attached to carbon 20 (C-20) have also been synthesized and tested. 1α-Hydroxy-2-methylene-19-nor-pregnacalciferol is described in U.S. Pat. No. 6,566,352 while 1α-hydroxy-2-methylene-19-nor-(20S)-homopregnacalciferol is described in U.S. Pat. No. 6,579,861 and 1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol is described in U.S. Pat. No. 6,627,622. All three of these compounds have relatively high binding activity to the vitamin D receptor and relatively high cell differentiation activity, but little if any calcemic activity as compared to 1α,25-dihydroxyvitamin D3. Their biological activities make these compounds excellent candidates for a variety of pharmaceutical uses, as set forth in the '352 , '861 and '622 patents.
An interesting modification of the vitamin D skeleton is removal of its C and D rings. The first compound (retiferol) lacking the C,D-substructure was disclosed by Kutner et al. ten years ago (Kutner et al., Bioorg. Chem., 23, 22 (1995). Several other des-C,D vitamin D3 derivatives, including 19-nor analogs, have been disclosed (Bauer et al., U.S. Pat. No. 5,969,190; Barbier et al., U.S. Pat. No. 6,184,422) and some of them (Ro 65-2299) have been reported to show improved biological activities [Hilpert and Wirz, Tetrahedron, 57, 681 (2001)].